Serotonin (5-HT) is a key modulatory neurotransmitter in the central nervous system. Early perturbations in the 5-HT system can have widespread and long-lasting behavioral effects. Disrupted 5-HT homeostasis has been implicated in the development of psychiatric disorders such as depression, anxiety disorders, drug addiction, and autism. Despite the successful characterization of the brain phenotype associated with the allele structure of the serotonin transporter (5-HTT) gene (SLC6A4) in adults, little is known about the developmental emergence of these phenotypes or about how these features interact with HPA function. The primary goal of the proposed study, therefore, is to explore characteristics of brain structure and function that are associated with genetic polymorphisms in a promoter region (5-HTTLPR) of the 5-HTT gene in children and adolescents. Given the relation between these polymorphisms and subsequent disorder, a secondary goal is to examine the possible relations among biological stress reactivity (indexed by cortisol response to stress) genotype, and measures of brain structure and function. The proposed research will combine self-report measures, neuroimaging assessments, indicators of HPA-axis functioning and reactivity, and genotyping to examine children's and adolescents'emotion regulation and reactivity to negative and/or threatening stimuli. Three specific aims are proposed: 1) to examine whether genetic variation in the serotonin transporter gene is associated with developmental changes in brain structure;2) to examine whether genotype moderates patterns of neural activation within brain regions that are involved in the processing of emotional material in children and adolescents;and 3) to examine stress reactivity in children and adolescents with different variants of the serotonin transporter gene. Participants in the proposed project will be 30 normally developing children between 9 and 11 years of age and 30 adolescents between 14 and 16 years of age. This project has significant relevance to public health. Genetic polymorphisms in the 5-HTT gene have been linked to morphological and functional changes in the adult brain that are similar to those that have been found to be associated with various forms of psychopathology (e.g., depression, anxiety disorder, post-traumatic stress disorder). By increasing our knowledge of the development of these anomalies, and by also integrating neural and cortisol measures with behavioral data, the proposed studies will provide a stronger scientific basis for understanding and integrating psychological, biological, and genetic aspects of the development of psychopathology.